In the industrialized world thrombotic complications are one of the major causes of death. Examples of conditions associated with pathological thrombus formation include deep vein thrombosis, venous and arterial thromboembolism, thrombophlebitis, coronary and cerebral arterial thrombosis, cerebral embolism, renal embolism and pulmonary embolism, disseminated intravascular coagulation, transient ischemic attacks, strokes, acute myocardial infarction, unstable angina, chronic stable angina, peripheral vascular disease, preeclampsia/eclampsia, and thrombotic cytopenic purpura. Also during or following invasive procedures, including insertion of endovascular devices and protheses, carotid endarterectomy, angioplasty, CABG (coronary artery bypass graft) surgery, vascular graft surgery, and stent placements, thrombotic and restenotic complications could occur.
Platelet adhesion and aggregation play a critical role in these intravascular thrombotic events. Platelets can be activated by mediators released from circulating cells and damaged endothelial cells lining the vessel or by exposed subendothelial matrix molecules such as collagen, or by thrombin, which is formed in the coagulation cascade.
Furthermore platelets can be activated under conditions of high shear blood flow in diseased vessels. Following activation, platelets, which normally circulate freely in the vasculature, and other cells, accumulate at the site of a vessel injury to form a thrombus and recruit more platelets to the developing thrombus. During this process, thrombi can grow to a sufficient size to partly or completely block arterial blood vessels.
In veins thrombi can also form in areas of stasis or slow blood flow. These venous thrombi can create emboli that travel through the circulatory system, as they easily detach portions of themselves. These traveling emboli can block other vessels, such as pulmonary or coronary arteries, which can result in the above-mentioned pathological outcomes such as pulmonary or coronary embolism.
In summary, for venous thrombi, morbidity and mortality arise primarily after embolization or distant blockade of vessels, whereas arterial thrombi cause serious pathological conditions by local blockade.
It was demonstrated that ADP (adenosine 5′-diphosphate) is an important mediator of platelet activation and aggregation. It plays a key role in the initiation and progression of arterial thrombus formation (Maffrand, et al, Thromb Haemostas (1988); 59: 225-230; Herbert, et al, Arterioscl Thromb (1993), 13: 1171-1179).
Upon activation by various agents, such as collagen and thrombin, ADP is released from blood platelets in the vasculature, as well as from damaged blood cells, endothelium or tissues. The ADP-induced platelet aggregation is triggered by its binding to two specific G protein-coupled receptors expressed on the plasma membrane of human platelets: P2Y1, and P2Y12. ADP binding to these receptors induces inhibition of adenylyl cyclase and modulation of intracellular signaling pathways such as influx and mobilization of intracellular Ca2+, activation of phosphoinositide-3 kinase (PI3K), shape change, secretion of other mediators, and platelet aggregation (Dangelmaier, et al. Thromb. Haemost. (2001), 85: 341-348). Activation by ADP results in the recruitment of more platelets and stabilization of existing platelet aggregates. Activation of the P2Y1 receptor leads to calcium mobilization from intracellular stores, platelet shape change and initiation of aggregation.
Activation of the P2Y12 receptor (also referred to as HORK3, P2RY12, SP1999, P2TAC, P2T or P2YAC) by ADP, leads to inhibition of adenylyl cyclase and activation of PI3K. Activation of P2Y12 is required for platelet secretion and stabilization of platelet aggregates (Gachet, Thromb. Haemost. (2001), 86, 222-232; Andre, et al., J. Clin. Invest., (2003), 112, 398-406).
There are several reports about directly or indirectly acting synthetic inhibitors of ADP-dependent platelet aggregation, which show antithrombotic activity.
The orally active thienopyridines, ticlopidine and clopidogrel, react covalently with the P2Y12 receptor and lead to an irreversible platelet inhibition in vivo. They also inhibit binding of radiolabeled ADP receptor agonist 2-methylthioadenosine 5′-diphosphate to platelets, and other ADP-dependent events (Savi, et al., Thromb Haemost. (2000), 84: 891-896).
In WO 02/098856 piperazine derivatives are disclosed, which are active as platelet adenosine diphosphate receptor antagonists. In EP 1698626 pyrazole derivatives are disclosed, which are active in platelet coagulation inhibition.
Houille et al. (WO 2005/000281 and WO 2005/002574) disclose pyrazolidinedione derivatives, useful as antithrombotic agents via inhibition of the platelet ADP receptor.
However, besides being effective P2Y12 antagonists, which antagonize the effect of endogenous ADP on its platelet ADP receptor, it is desirable that such antagonists also have further advantageous properties, for instance stability in plasma and liver and selectivity versus other receptors whose agonism or antagonism is not intended. There is an ongoing need for further low molecular weight P2Y12 antagonist, which are effective and have the above advantages as well.
The present invention satisfies the above needs by providing novel compounds of the formula I, which exhibit better P2Y12 antagonistic activity and are favorable agents with high bioavailability.